pH-responsive conformation with solubility changes is common behavior in biopolymers. The pH-responsive polymers consist of ionizable groups that can accept and donate protons in response to the environmental pH. As the environmental pH changes, the degree of ionization in a polymer bearing weakly ionizable groups is dramatically altered at a specific pH. (Eun Seok Gil, Samuel M. Hudson. Prog. Polym. Sci. 29, (2004) pp. 1173-1222). This rapid change in net charge of pendant groups causes an alteration in the hydrodynamic volume of the polymer chains. The transition from collapsed state to expanded state is due to the osmotic pressure exerted by mobile counter ions neutralizing the network charges (S. R. Tonge, B. J. Tighe, Adv Drug Deliv Rev 53 (2001), pp. 109-122).
The polymers containing ionizable groups in their backbone form polyelectrolytes in the aqueous system. There are two types of pH-responsive polyelectrolytes; weak polyacids and weak polybases. Weak polyacids such as poly(acrylic acid) get ionized at neutral and high pH (O. E. Philippova, D. Hourdet, R. Audebert and A. R. Khokhlov, Macromolecules 30 (1997), pp. 8278-8285). On the other hand, polybases like poly (4-vinylpyridine) get ionized at low pH. (V. T. Pinkrah, M. J. Snowden, J. C. Mitchell, J. Seidel, B. Z. Chowdhry and G. R. Fern, Langmuir 19 (2003), pp. 585-590). These vinyl pyridine polymers undergo a phase transition below pH 5 owing to protonation of pyridine groups (J. Gohy, B. G. G. Lohmeijer, S. K. Varshney, B. Decamps, E. Leroy, S. Boileau and U.S. Schubert, Macromolecules 35 (2002), pp. 9748-9755).
Most pH-responsive polymer systems are designed by combining functional domains to control the pH-responsive properties. Hydrophobically modified pH-responsive polymers have a sensitive balance between charge repulsion and hydrophobic interactions. Weak polybase based hydrogels have been investigated as drug delivery matrices for the release in stomach where the pH is acidic. These hydrogels release drugs at acidic pH in the stomach, because they are swollen.
A pH-sensitive chitosan-poly(Vinyl Pyridine) (PVP), semi-IPN was reported as a controlled release system for antibiotic delivery (M. V. Risbud, A. A. Hardikar, S. V. Bhat and R. R. Bhonde, J Control Release 68 (2000), pp. 23-30.).Antibacterial activities of polystyrene-block-poly(4-vinyl pyridine) and poly(styrene-random-4-vinyl pyridine)copolymers were investigated (Park, Eun Soo; Kim, Hun Sik; Kim, Mal Nam; Yoon, Jin San European Polymer Journal, 40(2004), pp. 2819-2822).
Copolymers of poly (4-vinylpyridine) with methyl acrylate were used as tablet coatings. These coatings required 2-4 hours for disintegration in water and 5-15 minutes for disintegration in artificial gastric juice. (Polymer tablet coatings. Tanabe Seiyaku Co. Ltd. (1959), GB 888131 19590725).
Homopolymers of 2-vinyl-, 4-vinyl-, 2-methyl-5-vinyl-, and 2-vinyl-5-ethylpyridine, were prepared by using either Benzoyl peroxide or potassium persulphate as catalyst. Copolymers of each of these compounds with styrene, vinyl acetate, Methyl acrylate, and acrylonitrile were synthesized. These polymers were excellent carriers for the release in gastric juice. (Utsumi, Isamu; Ida, Tadao; Takahashi, Shoji; Sugimoto, Norio. Journal of Pharmaceutical Sciences 50 (1961), pp. 592-7).
A diblock copolymer of 4-vinyl pyridine (4-VP) and tert-Bu acrylate was polymerized via RAFT. These polymers can serve as protected precursors of block polyampholytes. Upon cleavage of the protecting groups, a block copolymer that was responsive to pH and electrolyte concentration was formed. (Lokitz, Brad S.; Ayres, Neil; Convertine, Anthony J.; McCormick, Charles L. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, Pa., United States, Aug. 22-26, 2004).
The copolymerization of butyl acrylate was carried out with 2- and 4-vinylpyridine. Copolymer compositions were determined spectrophotometrically by monitoring vinyl pyridine absorption at 263 mμ. (Funt, B. L.; Ogryzlo, E. A. J. Polymer. Sci. 25, (1957), pp. 279-84.)
Biodegradable polyesters derived from aliphatic hydroxy carboxylic acids have been developed for medical applications such as surgical sutures, drugh delivery devices, tissue supports, and implants for internal bone fixation [S. W. Shalaby and A. Johnson In: S. W. Shalaby, Editor, Biomedical polymers: Designed-to-degrade systems, Carl Hanser Verlag, Munich (1994), pp. 1-34., R. L. Dunn In: J. O. Hollinger, Editor, Biomedical applications of synthetic biodegradable polymers, CRC Press, Boca Raton (1995), pp. 17-31., V. Maquet and R. Jerome Mater. Sci. Forum 250 (1997), pp. 15-42).
Most of these materials are made from high-molecular-weight linear polyesters like polylactides, polyglycolides and their copolymers (D. E. Perrin and J. P. English In: A. J. Domb, J. Kost and D. M. Wiseman, Editors, Handbook of biodegradable polymers, Harwood Academic Publishers, Amsterdam (1997), pp. 3-27).
Less attention has been paid to oligomeric esters, because these oligomers normally do not have the mechanical and thermal properties required for sutures or implants. Recent work on the synthesis of liquid or low melt oligolactones offers an interesting approach to a new class of biodegradable materials usable for example to produce injectable drug delivery systems, implant coatings or soft tissue augmentations (G. Coullerez, C. Lowe, P. Pechy, H. H. Kausch and J. Hilborn J. Mater. Sci: Mater. Med. 11 (2000), pp. 505-510). In addition, biodegradable polymer networks and composites can be prepared from these oligoesters terminated with unsaturated functional groups (D. K. Han and J. A. Hubbell Macromolecules 30 (1997), pp. 6077-6083).
A series of novel linear and star-shaped oligolactide macromers were prepared and used for the fabrication of highly porous polymer network scaffolds of controlled shape. In vitro studies on the cultivation of osteoblasts on these materials demonstrated that the prepared polymer networks possess excellent biocompatibility and that they are well suited as scaffolds for bone tissue engineering. (Matthias Schnabelrauch, Sebastian Vogta, Yves Larcherb and Ingo Wilkeb Biomolecular Engineering, 19 (2-6), (2002), pp. 295-298).
Cyclic tin alkoxides were used to initiate controlled ring-opening polymerization (ROP) of L-Lactide, yielding a series of lactide macromonomers. Double bond of the initiator was successfully incorporated into the synthesized macromonomers which is well-suited for postpolymerization into a brush like polymer. (Ryner, M.; Finne, A.; Albertsson, A. C.; Kricheldorf, H. R. Macromolecules 34, (2001), pp. 7281-7287.) This unsaturated macromonomer provided a variety of opportunities for further modifications. The incorporated C═C double bond was oxidized into epoxides. (Finne, Anna; Albertsson, Ann-Christine. Journal of Polymer Science, Part A: Polymer Chemistry 42(3), (2004), pp. 444-452)
Poly (D, L) lactide diacrylate macromer was used to develop a new family of biodegradable hydrogels with photo-crosslinked dextran derivative of allyl isocyanate. The changes in thermal and mechanical properties of these hydrogels as function of dextran and lactide macromer composition were investigated. (Zhang, Yeli; Chu, Chih-Chang. Journal of Materials Science: Materials in Medicine 13(8), (2002), pp. 773-781).
A series of temperature and pH-sensitive hydrogels based on poly (2-ethyl-2-oxazoline) and three-arm poly (D, L-lactide) macromer were synthesized via photo-copolymerization. Lactide macromer was synthesized by first reacting lactide with Glycerol and then reacting the three arm poly-lactide with methacryloyl chloride and triethylamine. (Wang, Chau-Hui; Hsiue, Ging-Ho. Journal of Polymer Science, Part A: Polymer Chemistry 40(8), (2002), pp. 1112-1121). Novel difunctional oligolactone macromers have been synthesized by ring-opening oligomerization of various lactones (L-lactide, glycolide, p-dioxanone) in the presence of suitable diols (propane-1, 2-diol, dianhydro-D-glucitol) and subsequent end capping of the formed oligolactones with methacrylate moieties. Highly porous scaffolds were fabricated from these macromers. The oligolactide based polymer networks possess excellent biocompatibility and are promising candidates as scaffolds in bone tissue engineering. (Haris, Parvez I.; Vogt, S.; Berger, S.; Wilke, I.; Larcher, Y.; Weisser, J.; Schnabelrauch, M. Bio-Medical Materials and Engineering 15(1, 2), (2005), pp. 73-85)
To date much work has been done on copolymerization of acrylate monomers with polyacids or polybases to get pH sensitive polymers. Such copolymers are high molecular weights and they are being used in variety of applications described above. Methacrylate oligomers and unsaturated lactide oligomers were synthesized to obtain low molecular weight macromers of lactide and were used as biodegradable drug delivery systems after proper modification. Mainly they were cross linked with suitable monomers to get hydrogels and their biodegradability and swelling behavior was studied. Scaffolds were also designed and were investigated for their biocompatibility. But no effort was made to copolymerize lactide macromer with polybases or polyacids to get pH sensitive polymers of low molecular weight.